tbuckley/cabot-search huggingface dataset:
Abstract IA006: EMT-induced tumor plasticity in cancer metastasis
Authors: Sendurai A Mani
Journal: Cancer Research (2023)

Abstract Advancements in diagnosis and treatment help save cancer patients if the patient presents with local disease. However, the survival probability drops significantly when the tumor metastasizes to other organs. Cancer stem cells (CSCs) are responsible for developing resistance to chemotherapy, tumor relapse, and metastasis. We and others found that the latent embryonic program epithelial to mesenchymal transition (EMT), known to induce mesenchymal properties, including increased migration and invasion, can also induce stem cell properties in cancer cells. This finding postulates that the tumor is inherently capable of generating CSCs de novo and promoting plasticity and heterogeneity. Using syngeneic orthotopic tumor models, we found that CD8+ T cells play a vital role in regulating metastasis besides plasticity in tumor cells. This finding suggests that targeting EMT-signaling pathways and immune cells may provide a window of opportunity to treat metastasis, chemoresistance, and tumor relapse. Citation Format: Sendurai A Mani. EMT-induced tumor plasticity in cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA006.
Abstract IA022: Cell archetypes in human brain metastases: Connecting programs in tumor cells with the microenvironment
Authors: Hugo Gonzalez, Wenbin Mei, Isabella Robles, Catharina Hagerling, Breanna Allen, Trine Hauge Okholm, Ankitha Nanjaraj, Tamara Verbeek, Sandhya Kalavacherla, Merel van Gogh, Stephen Georgiou, Mariza Daras, Joanna J. Phillips, Matthew H. Spitzer, Jeroen P. Roose, Zena Werb
Journal: Cancer Research (2023)

Abstract Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of &amp;gt;100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, that co-exist within each metastatic tumor, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our study provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits. For more details please refer to the original study: H. Gonzalez, et al. Cellular architecture of human brain metastases Cell, 185 (2022), pp. 729-745. Citation Format: Hugo Gonzalez, Wenbin Mei, Isabella Robles, Catharina Hagerling, Breanna Allen, Trine Hauge Okholm, Ankitha Nanjaraj, Tamara Verbeek, Sandhya Kalavacherla, Merel van Gogh, Stephen Georgiou, Mariza Daras, Joanna J. Phillips, Matthew H. Spitzer, Jeroen P. Roose, Zena Werb. Cell archetypes in human brain metastases: Connecting programs in tumor cells with the microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA022.
Abstract B010: The effects of tumor cell-secreted factors on endothelial cell junction phenotype
Authors: Ariana Joy L. DeCastro, Lauren Griffith, Kimberly Stroka
Journal: Cancer Research (2023)

Abstract Triple negative breast cancer (TNBC) is subtype of breast cancer that has no expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC metastasizes to specific tissues such as brain and bone in a process termed organotropism. In this process, TNBC cells cross the vascular endothelium; transport across endothelial cells is, in part, regulated by cell-cell junctions. The TNBC cell secretome has been shown to contain factors such as vascular growth factor (VEGF) and matrix metalloproteinases (MMPs) that could play a role in altering endothelium permeability. Prior work by us has shown that VEGF in tumor conditioned media can alter endothelial cell junction phenotype in human brain microvascular endothelial cells. Given the various factors present in tumor conditioned media (TCM), we hypothesized that both VEGF and MMPs are present at distinct levels in conditioned media derived from brain- or bone-seeking TNBC cells and that these factors alter junction phenotype in human umbilical vein endothelial cells. We quantified levels of VEGF and MMPs 1 and 9 in tumor conditioned media from parental, brain-seeking, and bone-seeking MDA-MB-231 cells. Our results show that brain-seeking tumor cell conditioned media reduces VE-cadherin continuous junction coverage compared to conditioned media from parental or bone-seeking cells. VE-Cadherin junctions also have decreased junction widths in response to tumor conditioned treatment from brain-seeking MDAs. These results show that secreted factors from TNBC cells have a modest impact on endothelium junction integrity, and future work will quantify changes in endothelium permeability to test barrier function. This work will contribute to a further understanding of TNBC organotropic metastasis and more effective targeted therapeutics to prevent disease progression. Citation Format: Ariana Joy L. DeCastro, Lauren Griffith, Kimberly Stroka. The effects of tumor cell-secreted factors on endothelial cell junction phenotype [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B010.
Abstract IA017: The elusive ‘metastasis driver’: Is it hiding in plain sight
Authors: Ben Stanger
Journal: Cancer Research (2023)

Abstract Recurrent single nucleotide mutations are a common feature of primary tumor evolution, where mutations in genes such as KRAS, APC, TP53, and BRAF are important drivers of malignancy. Efforts to identify comparable mutations that are exclusive to metastatic lesions - so-called 'metastasis drivers' - have been harder to find. However, the search for such metastasis-enabling genetic events has largely been limited to single nucleotide variants rather than chromosomal alterations (copy number gains and losses), which are far more common in advanced tumors. In this study, we used a stochastic mouse model of pancreatic cancer which gives rise to both highly metastatic and poorly metastatic tumors to interrogate the molecular correlates of metastatic heterogeneity. Our analysis revealed that focal amplifications of the MYC oncogene, but not other oncogenic drivers, were associated with the highly metastatic phenotype. Moreover, highly metastatic tumors exhibited elevated levels of MYC protein and greater expression of MYC target genes. This relationship between MYC copy number and metastasis was also observed in human samples, where MYC amplifications were found in 11% of metastases but fewer than 2% of primary tumors. Mechanistically, MYC enhances metastasis by recruiting pro-invasive macrophages, leading to greater vascular intravasation of tumor cells. These results nominate MYC as a bona fide metastasis driver gene and highlight the importance of considering copy number alterations in the evaluation of genetic mediators of metastasis. Citation Format: Ben Stanger. The elusive ‘metastasis driver’: Is it hiding in plain sight [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA017.
Abstract IA024: Cellular plasticity during metastatic colony formation in patients
Authors: Melanie Werner-Klein
Journal: Cancer Research (2023)

Abstract Systemic cancer spread is a process whose complexity is only poorly understood. We have learned over the past years that metastatic dissemination starts very early in the evolution of a malignant clone of most cancers and that disseminated cancer cells (DCC) continue to acquire genomic alterations at the distant site. Consequently, it seems plausible that cellular phenotypes change during metastatic colony formation as well, although the impact of genotype changes on the cellular phenotypes is not clear at all. We studied this process in malignant melanoma, exploiting the unique chance that routine sentinel lymph node (SLN) biopsies provide for a cancer that is diagnosed much earlier and at smaller size than most other cancers. Moreover, mouse models suggest that lymph nodes serve as exit routes for systemic dissemination of cancer cells and that their colonization indues tumor-immune tolerance promoting distal metastasis. Melanoma DCC enter SLNs and may or may not give rise to a metastatic colony. We therefore first assessed in a large patient cohort comprising more than 500 early-stage melanoma patients, which melanoma marker is best suited to identify candidate metastasis founder cells and then progressed to provide their detailed molecular characterization. We found that melanoma cellular phenotypes indeed change over metastatic colony formation, indicating that differential molecular stage-specific targeting may be required to prevent metastasis formation. Of note, we observed mechanisms of very early immune suppression via DCC-derived EVs suggesting early DCC must find immune-escape strategies at the metastatic site. Citation Format: Melanie Werner-Klein. Cellular plasticity during metastatic colony formation in patients [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA024.
Abstract IA019: Unique features and dependencies of brain metastases
Authors: Michael A. Davies
Journal: Cancer Research (2023)

Abstract Metastasis to the central nervous system (CNS), including the brain and leptomeninges, is one of the most common and devastating complications of metastatic melanoma. Metastasis to the brain is detected in 40-60% of stage IV melanoma patients. CNS metastasis remains a leading cause of morbidity and mortality from this disease, and a common site of therapeutic resistance. Improving outcomes in these patients is made challenging by the relatively limited understanding of the features of these tumors- and exacerbated by the frequent exclusion of patients with brain metastases from clinical trials. There is growing evidence that brain metastases from melanoma and other cancers harbor/share unique features that drive the aggressive nature and therapeutic resistance of these tumors. Studies across cancer types have revealed differences in the immune microenvironment of the tumors, as well as their oncogenic mutations and activation of key signaling pathways. Recently, multiple laboratories have identified unique metabolic features of these tumors. Several of these studies have identified novel metabolic dependencies of brain metastases- and suggest a novel paradigm of therapeutic agents (and clinical trials) that are expected to achieve greater benefit in patients with CNS involvement than without. Such findings are leading to the development of both clinics and clinical trials focused on brain metastases across cancer types. They are also leading to further investigations to determine the role of these features in the initiation, progression, and resistance of brain metastases. Citation Format: Michael A. Davies. Unique features and dependencies of brain metastases [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA019.
Abstract B046: MLL1 regulates cytokine-driven cell migration and metastasis
Authors: Praful R. Nair, Ludmila Danilova, Estibaliz Gómez-de-Mariscal, Dongjoo Kim, Rong Fan, Arrate Muñoz-Barrutia, Elana Fertig, Denis Wirtz
Journal: Cancer Research (2023)

Abstract Cell migration, particularly in three-dimensional (3D) environments, is a critical requirement for metastasis - the spread of cancer cells from a primary tumor to distant sites. Despite causing the vast majority of cancer-related deaths, targeting metastasis remains challenging clinically. Cancer cell migration can be triggered and maintained by elevated levels of cytokines, which are presumed to be predominantly secreted by immune cells in the tumor microenvironment. However, recent work has highlighted the importance and impact of cytokine production by cancer cells themselves. While the signaling cascades that regulate cell migration have been studied extensively, the epigenetic regulation of cell migration is still poorly understood. MLL1 is a histone methyltransferase, which along with its scaffold protein Menin, is integral to methylation at the histone 3 lysine 4 (H3K4) site. Here, we show that the MLL1-Menin interaction is essential for the migration of cancer cells and that the disruption of this interaction impairs cell migration and metastasis. MLL1 depletion reduces 3D cell migration in vitro and led to lesser metastatic burden and prolonged survival in vivo. Reduced lung metastatic burden was observed even after accounting for the difference in the growth rate of primary tumors. Mechanistically, MLL1-Menin interaction controls actin filament assembly via the IL-6/pSTAT3/Arp3 axis and acto-myosin contractility via the TGF-β1/Gli2/ROCK1/2/pMLC2 axis, which together regulate dynamic protrusion generation and 3D cell migration. MLL1-Menin inhibition also decreases cell proliferation by inhibiting mitosis and cell cycle-related pathways. MLL1 depletion decreases primary tumor growth, metastatic spread, and metastatic outgrowth in mouse models of triple-negative breast cancer (TNBC), thus improving survival. Combining an MLL1-Menin inhibitor with Paclitaxel, a standard TNBC chemotherapeutic, abrogated tumor growth and metastasis in a syngeneic TNBC mouse model. Overall, our studies show that MLL1 is an epigenetic regulator of 3D cancer cell migration, which exerts its effects by controlling the production of the key cytokines IL-6 and TGF-β1. Our in vivo studies demonstrate the potential of targeting the MLL1-Menin interaction in metastasis prevention and its potential to be combined with currently administered chemotherapeutics. Citation Format: Praful R. Nair, Ludmila Danilova, Estibaliz Gómez-de-Mariscal, Dongjoo Kim, Rong Fan, Arrate Muñoz-Barrutia, Elana Fertig, Denis Wirtz. MLL1 regulates cytokine-driven cell migration and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B046.
Abstract PR008: Timing complex copy number gains in whole genome duplicated tumors
Authors: Toby M. Baker, Siqi Lai, Stefan Dentro, Maxime Tarabichi, Peter Van Loo
Journal: Cancer Research (2023)

Abstract The accumulation of genetic copy number aberrations is a process common to the development of many cancers. Tumors that have undergone a whole genome duplication (WGD) are known to have high degrees of genomic instability and often contain genomic regions that have undergone a series of copy number gains resulting in multiple copies of both alleles. Metastases are known to have an even greater rate of WGDs and general genomic instability. WGDs provide a powerful handle to time genetic events, such as single nucleotide variants or copy-number aberrations, in tumor evolution. However, the relative timing of copy number gains in whole genome duplicated tumors is complicated by the fact that there are multiple plausible route histories that could give rise to them. Typically, the most parsimonious event history is assumed to take place but this has never been validated. Here we describe a method, GRITIC, that overcomes this problem by evaluating all possible histories that could result in a given copy number state and determining the timing of the most likely series of gains. GRITIC allows the gains leading to any copy number state to be inferred. On a representative simulated cohort, it accurately measures the timing of complex copy number gains. By applying GRITIC to 6,010 primary and metastatic tumor samples from the Pan-Cancer Analysis of Whole Genomes and Hartwig Medical Foundation datasets, we find that the principle of maximum parsimony is violated in at least 25% of all copy number gains in whole genome duplicated tumors, with gains occurring both much earlier and later than thought under this assumption. We also find evidence for punctuated bursts of gains in WGD tumors, independent of the duplication itself. Finally, GRITIC allows us to look at the influence of WGD on copy-number events by comparing pre- and post-WGD copy number aberration landscapes. We find that the frequency with which different chromosome arms are gained before a WGD is highly correlated with the frequency that they are gained post-WGD. In contrast, the correlation between pre- and post-WGD losses is much smaller. We suggest that this indicates that a genome duplication changes the evolutionary trajectories of copy number losses but not gains. As an exception to this trend, chromosome 8 was disproportionately likely to be gained pre-WGD in metastatic prostate cancer as well as 1q in both breast and liver cancers. Altogether, GRITIC allows for a more accurate inference of evolutionary histories in different cancer types and better insights into the early genomic events that occur in tumors that underwent a WGD. Citation Format: Toby M. Baker, Siqi Lai, Stefan Dentro, Maxime Tarabichi, Peter Van Loo. Timing complex copy number gains in whole genome duplicated tumors [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR008.
Abstract A045: Examining the role of RNA:DNA hybrids (r loops) in glioblastoma multiforme cell motility and invasion
Authors: Julio C. Morales, Tuyen T. Dang
Journal: Cancer Research (2023)

Abstract Glioblastoma multiforme (GBM) is a highly aggressive brain cancer. The standard course of treatment is a combination of radiation and chemotherapy. Even with the dual treatment, the 5-year survival rate of patients with GBM is between 4-10%. A possible cause of the low survival rate for GBM patients is the presence of motile neoplastic cells with efficient DNA repair abilities. Thus, the two major obstacles to treating GBMs is 1) the tumors inherent invasive nature and 2) the recurrent tumors ability to acquire treatment resistance. As such, gaining a better understanding of the mechanisms mediating GBM recurrence would allow us to design better treatment strategies for patients. We have found that the 5’-3’ exoribonuclease XRN2 is upregulated in GBMs as compared to normal and other brain cancer types. While XRN2 is traditionally associated with the process of transcription termination, our published work has defined a role for XRN2 in the DNA damage response. Our group has shown that loss of XRN2 sensitizes to a variety of DNA damaging agents but in particular ionizing radiation. Previously, we have shown that XRN2 is required for DNA repair, specifically double stranded break (DSB) repair. Loss of XRN2 impairs both the non-homologous end-joining and homologous recombination DSB repair pathways. Loss of XRN2 also results in increased spontaneous DSB formation, chromosomal aberrations and RNA:DNA hybrid (R-loop) formation. In addition to a role in the DNA damage response, we found that loss of XRN2 is required for GBM cell motility, invasion through a matrix and decreased tumor volume in mouse models. Interestingly, R-loop formation can affect gene expression by modulating the access of genes to transcription factors, miRNA transcription, and methylation status of genes. To gain a better understanding of how XRN2 modulates gene expression, we conducted RNA-Seq analyses of GBM cell lines with and without XRN2 expression and found that XRN2 can regulate genes involved in cell movement, cell development and cellular organization programs. Consistent with our findings that XRN2 impairs DNA damage and tumor invasion; XRN2 loss results in R-loop formation in promoters of genes important for tumor invasiveness and DNA repair such as FOXM1 and Cyclin B1. These data suggest that the regulation of R-loop formation is an important determinant in tumor progression. Citation Format: Julio C. Morales, Tuyen T. Dang. Examining the role of RNA:DNA hybrids (r loops) in glioblastoma multiforme cell motility and invasion [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A045.
Abstract B043: Tissue Factor Pathway Inhibitor (TFPI), a novel invasion and therapy target in glioblastoma multiforme
Authors: Tuyen T. Dang, Julio C. Morales
Journal: Cancer Research (2023)

Abstract Glioblastoma multiforme (GBM) is a deadly brain cancer with a 4-10% five-year survival rate. Even with the advent of temozolomide and tumor treating fields, at best GBM patients can hope for a median survival of approximately 25 months. The major cause of poor survivorship is the recurrence of inoperable therapy resistant secondary tumors. With the poor survivorship, there is an urgent need for novel therapy regimens. We propose a novel therapy and metastatic target for GBM treatment. Tissue Factor Pathway Inhibitor (TFPI) is a serine proteinase inhibitor. Classically, TFPI inhibits FXa and/or TF-VIIa to reduce blood coagulation. Recently, TFPI expression have been correlated with solid tumors such as breast, pancreatic, colorectal and brain tumors. However, it is unknown how TFPI contributes to cancer disease. We observed that TFPI increased expression correlated with GBM tumor samples. Additionally, GBM patients with high expression of TFPI had a poorer survivorship than those with low expression of TFPI. Using live cell imaging, we found that TFPI is required for cell motility, an initial and required step in cancer cell invasion. Additionally, we found that loss of TFPI increased 53bp1 foci formation. Increased 53bp1 foci formation is an indication of defunct DNA double stranded break repair. We found that loss of TFPI sensitizes cells to ionizing radiation another indication of a dysfunctional DNA double stranded break repair program. We found that loss of TFPI sensitizes cells to Parp-1 inhibition, a hallmark of a defunct homologous recombination repair program. Homologous recombination and non-homologous end-joining are the two major repair pathways for DNA double stranded breaks. Based on these preliminary data, we hypothesize that TFPI plays role in motility/invasion and DNA repair, which leads to therapy resistance and metastasis in GBM. TFPI is an attractive radio-sensitizer for GBM treatment since radiation is a first-line therapy modality. Additionally, Parp-1 inhibition is currently in clinical trials for GBM treatments. Lastly, there is an FDA approved inhibitor for TFPI, ANDEXXA and several TFPI antibodies in clinical trials. Our future endeavors are to elucidate the mechanisms by which TFPI regulates DNA repair and cancer cell invasion. These findings will lay down the foundation for using TFPI inhibitors as a concurrent treatment plan to standard of care. Citation Format: Tuyen T. Dang, Julio C. Morales. Tissue Factor Pathway Inhibitor (TFPI), a novel invasion and therapy target in glioblastoma multiforme [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B043.